This invention relates to new and valuable taste-masking compositions wherein the bitter taste and/or aftertaste of a bitter pharmaceutical agent is reduced. This invention further relates to taste-masked pharmaceutical compositions containing a bitter pharmaceutical agent, said compositions being capable of being chewed or imbibed without the production of a bitter taste or aftertaste.
A wide variety of active pharmaceutical agents exhibit the undesirable characteristic of bitter taste production either during or immediately after oral administration. Among these are included such diverse medicinal agents as acetaminophen, ampicillin, azithromycin, chlorpheniramine, cimetidine, dextromethorphan, diphenhydramine, erythromycin, ibuprofen, penicillin, phenylbutazone, psuedoephedrine, ranitidine, spironolactone and theophylline. The azalide and erythrolide antibiotics are two particularly bitter tasting classes of pharmaceutical agents, and the azalide azithromycin is among the most bitter pharmaceutical agents known.
The bitter flavor of a bitter pharmaceutical agent in a liquid suspension is inevitably detected during the drinking process or immediately after swallowing. Additionally, the bitter flavor of a bitter pharmaceutical agent in a tablet, capsule, suspension or other oral dosage form may be detected upon administration if the bittering agent is brought into contact with the taste buds as by overlong holding of the dosage form in the mouth, by inadvertent chewing of the dosage form or by some other release of the bitter pharmaceutical agent.
The administration of an oral dosage form is generally the preferred route of administration of many of the pharmaceutical agents recited hereinabove because it provides for easy, low-cost administration. However, patient compliance can sometimes be a factor when a patient is requested to swallow a tablet, capsule or suspension. Patients give many reasons for their refusal or inability to accept the oral administration of a medicinal such as unattractive presentation, overlarge size, bad taste or simple fear that an unchewed dosage form may catch in the throat. Patients who have difficulties with oral dosage forms often exhibit a gag reflex which effectively prevents oral administration. This problem is common in, but not specific to, children.
It is therefore desirable to formulate pharmaceutical agents in such a way that the above-mentioned problems are overcome. Thus, chewable tablets have been developed which have been shown to increase patient compliance in both children and others who have a problem swallowing whole tablets or capsules. However, quite often a pharmaceutical agent is so bitter-tasting that it cannot be tolerated when chewed, and the unpleasant taste or aftertaste imparted by the bittering agent will serve to disincline patients from self-administering the oral dosage form. There is, therefore, a need to mask the taste of bitter pharmaceutical agents such that the bitter flavor is reduced or eradicated from any oral dosage form which may be required for administration.
Conventionally, sweeteners and flavorants have been used in taste-masking. These agents generally work by providing a secondary flavor to the composition which it is hoped will overwhelm any bitter flavor. This technique is sometimes able to mask mildly bitter pharmaceuticals, but the traditional sweeteners are not effective in masking the bitter flavor of powerfully bitter pharmaceutical agents such as azithromycin.
Alternative approaches which have been used to mask the bitter flavor of certain pharmaceuticals include microencapsulating the unpleasant tasting active agent in a coating of ethyl cellulose or a mixture of ethyl cellulose and hydroxypropyl cellulose or other cellulose derivatives to provide chewable taste-masked dosage forms. These prior art products, however, suffer from the disadvantage that the polymer coating releases the active agent in an inconsistent fashion and may not provide immediate (or timely) release. Further, the use of said cellulose derivatives in and of themselves is quite often insufficient to provide adequate taste-masking of potently bitter active agents such as azithromycin.
Azithromycin is the generic (United States Adopted Names) name for 9-deoxo-a-aza-9a-methyl-9a-homoerythromycin A, a broad spectrum antibiotic which has one of the most potently bitter flavors known. Azithromycin is disclosed by Kobrehel et al., U.S. Pat. No. 4,517,539, the disclosure of which is hereby incorporated by reference. Azithromycin is also known as N-methyl-11-aza-10-deoxo-10-dihydroerythromycin.
The aforementioned bitter taste of azithromycin poses a serious patient compliance problem unless formulated in an oral dosage form in which said bitter taste is masked or reduced. Currently, azithromycin is being marketed as a non-chewable capsule. This presents a problem for some patients, as indicated hereinabove.
It is therefore an object of this invention to provide a method of reducing the bitterness of bitter pharmaceutical agents.
It is a further object of this invention to provide an orally administrable liquid and a chewable, taste-masked formulation of various bitter pharmaceutical agents.
It is a still further object of this invention to provide a chewable, taste-masked formulation of azithromycin which does not exhibit the bitter, unpleasant taste characteristic of azithromycin.